Background: Thyroid cancer is one of the fastest growing cancer diagnoses in the United States. Non-medullary thyroid cancer accounts for 95% of all thyroid cancer cases. Up to 8% of all non-medullary thyroid cancers are hereditary. Familial non-medullary thyroid cancer (FNMTC) is more aggressive than sporadic disease. The best approach for screening at risk family members for FNMTC is unknown. The goal of this project is to determine the natural history and best screening strategy for FNMTC, and to identify susceptibility gene(s) for FNMTC. Summary: This is a prospective study of individuals with or at risk for non-medullary thyroid cancer. Individuals will be studied over time within the context of their families in order to quantify prospective risks of cancers in family members, to establish the natural history of FNMTC, define the spectrum of diseases within the families, to identify precursor states, to try to assess the contribution of genetic and environmental components of risk, and to develop effective screening strategies. Our ongoing analysis of screening at risk individuals shows that the prevalence of thyroid nodules and thyroid cancer is much higher than the general population. The higher prevalence of thyroid neoplasm/cancer in kindred is even more dramatic in younger members at risk. We recently have identified FNMTC cancer susceptibility genes by next generation sequencing of germline DNA. This gene functions as a dominant-negative tumor suppressor gene and is present in 4.7% of patients with nonmedullary thyroid cancer. We have also identified two additional candidate susceptibility genes in additional kindred with FNMTC that we are currently characterizing their function as tumor suppressor genes or oncogenes. Our findings thus far suggest that FNMTC is a polygenetic inherited familial cancer syndrome.